An Investigation on Glucuronidation Metabolite Identification, Isozyme Contribution, and Species Differences of GL-V9 In Vitro and In Vivo

Xing, Haizhou; Kong, Dexuan; Chen, Ning; Kong, Ying; Ren, Chang E.; Cheng, Yujie; Cai, Hui; Wang, Jubo; Zhao, Di; Li, Ning; Chen, Xijing; Li, Zhiyu; Lu, Yang

doi:10.3390/molecules24081576

Cited by 5 publications

(11 citation statements)

References 43 publications

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“…UGTs are abundant in the liver and intestine [101]. These membrane-bound enzymes of the endoplasmic reticulum account for the metabolism of more than 35% of drugs [102,103]. Human UGT enzymes are categorized into four families, namely: UGT1, UGT2, UGT3, and UGT8.…”

Section: Glucuronidation and Its Kineticsmentioning

confidence: 99%

In Vitro Drug Metabolism Studies Using Human Liver Microsomes

Gajula¹,

Vora²,

Dikundwar³

et al. 2023

Dosage Forms - Innovation and Future Perspectives

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Metabolism of most pharmaceutical drugs occurs in the liver. In drug metabolism, enzymes convert drugs to highly water-soluble metabolites to facilitate excretion from the body. Thus, in vitro models for studying drug metabolism usually target hepatocytes or subcellular liver fractions like microsomes, cytosols, or S9 fractions with high concentrations of specific enzymes. The most popular subcellular fraction used during drug discovery tends to be the microsomes, as these are easy to prepare and store, are amenable to high throughput screening, and are a relatively low-cost option. Understanding the metabolic stability and kinetics of glucuronidation of an investigational drug is crucial for predicting the pharmacokinetic parameters that support dosing and dose frequency. This chapter provides detailed information about metabolite profiling, metabolic stability, glucuronidation kinetics, reactive metabolites identification, CYP enzyme inhibition, and general protocols using human liver microsomes.

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Section: Glucuronidation and Its Kineticsmentioning

confidence: 99%

In Vitro Drug Metabolism Studies Using Human Liver Microsomes

Gajula¹,

Vora²,

Dikundwar³

et al. 2023

Dosage Forms - Innovation and Future Perspectives

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“…As baicalein and wogonin, oroxylin A is also an important component of Scutellaria species, but is also present in species of Oroxylum , Capparis , Ardisia , Stachys , and Eucommia genera [20]. GL-V9 is a synthetic derivative of wogonin, with antitumor activity shown in various in vitro models [21], whereas BA-j is a synthetic derivative of baicalin (8-hydroxypiperidinemethyl-baicalein) with similar activity [22].…”

Section: B-ring Unsubstituted Flavonesmentioning

confidence: 99%

Pharmacokinetics of B-Ring Unsubstituted Flavones

et al. 2019

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B-ring unsubstituted flavones (of which the most widely known are chrysin, baicalein, wogonin, and oroxylin A) are 2-phenylchromen-4-one molecules of which the B-ring is devoid of any hydroxy, methoxy, or other substituent. They may be found naturally in a number of herbal products used for therapeutic purposes, and several have been designed by researchers and obtained in the laboratory. They have generated interest in the scientific community for their potential use in a variety of pathologies, and understanding their pharmacokinetics is important for a grasp of their optimal use. Based on a comprehensive survey of the relevant literature, this paper examines their absorption (with deglycosylation as a preliminary step) and their fate in the body, from metabolism to excretion. Differences among species (inter-individual) and within the same species (intra-individual) variability have been examined based on the available data, and finally, knowledge gaps and directions of future research are discussed.

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“…Flavonoids and their derivatives have been extensively documented for their wide‐ranging bioactivities, including anticancer, immunomodulatory, antiallergic, and antioxidant properties (Nijveldt et al, 2001; Wen et al, 2017). Nevertheless, the pharmacokinetic properties of numerous flavonoids, including wogonin, are deemed unsatisfactory due to factors such as poor water solubility, susceptibility to hydrolysis, and low bioavailability (Xing, Kong, Ning, Kong, et al, 2019). In recent years, researchers have made efforts to design and synthesize a series of derivatives with novel structures, aiming to enhance pharmacological activity and rectify the limitations of the original drug prototype.…”

Section: Introductionmentioning

confidence: 99%

“…GL‐V9, a derivative of wogonin, has garnered increasing attention due to its noteworthy bioactivities, particularly its enhanced antitumor efficacy compared with wogonin (Gu et al, 2021; Hu et al, 2019; Xing, Kong, Ning, Kong, et al, 2019; Yang et al, 2020). Li et al (2011) reported half‐maximal inhibitory concentration (IC 50 ) values of 35.2 ± 3.2 and 132.4 ± 25.3 μM for GL‐V9 and wogonin treatment on HepG2 cells, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…This analysis provides a scientific foundation for the clinical application of GL‐V9. Xing, Kong, Ning, Kong, et al (2019) indicated that the glucuronidation reaction primarily occurred at the C5‐OH group, resulting in 5‐O‐glucuronide GL‐V9 as the sole glucuronide metabolite and the major phase II metabolite of GL‐V9. The pharmacological efficacy of GL‐V9 has been established; however, limited research has delved into the in vivo pharmacokinetics, tissue distribution, and excretion features of GL‐V9 and its metabolite, 5‐O‐glucuronide GL‐V9.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics, tissue distribution, and excretion study of GL‐V9 and its glucuronide metabolite 5‐O‐glucuronide GL‐V9 in Sprague–Dawley rats

Zhang,

Liu,

Sang

et al. 2024

Biomedical Chromatography

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The objective of this study is to explore the pharmacokinetics, tissue distribution, and excretion patterns of GL‐V9 and its glucuronide metabolite, 5‐O‐glucuronide GL‐V9, following the administration of GL‐V9 to Sprague–Dawley (SD) rats. In this research, we developed and validated rapid, sensitive, and selective ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) methods for quantifying GL‐V9 and 5‐O‐glucuronide GL‐V9 in various biological samples, including SD rat plasma, tissue homogenate, bile, urine, and feces. Quantification of GL‐V9 and 5‐O‐glucuronide GL‐V9 in plasma, tissue homogenate, bile, urine, and feces was performed using the validated LC–MS/MS methods. The bioavailability of GL‐V9 in SD rats ranged from 6.23% to 7.08%, and both GL‐V9 and 5‐O‐glucuronide GL‐V9 exhibited wide distribution and rapid elimination from tissues. The primary distribution tissues for GL‐V9 and 5‐O‐glucuronide GL‐V9 in rats were the duodenum, liver, and lung. GL‐V9 was predominantly excreted in urine, while 5‐O‐glucuronide GL‐V9 was primarily excreted in bile. GL‐V9 exhibited easy absorption and rapid conversion to its glucuronide metabolite, 5‐O‐glucuronide GL‐V9, following administration.

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An Investigation on Glucuronidation Metabolite Identification, Isozyme Contribution, and Species Differences of GL-V9 In Vitro and In Vivo

Cited by 5 publications

References 43 publications

In Vitro Drug Metabolism Studies Using Human Liver Microsomes

In Vitro Drug Metabolism Studies Using Human Liver Microsomes

Pharmacokinetics of B-Ring Unsubstituted Flavones

Pharmacokinetics, tissue distribution, and excretion study of GL‐V9 and its glucuronide metabolite 5‐O‐glucuronide GL‐V9 in Sprague–Dawley rats

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